Zinc-L-Carnosine (Polaprezinc): Ulcer, Gut and Safety Evidence

Polaprezinc has a gastric-ulcer medicine indication in Japan. The reviewed human research concerns specific ulcers, antibiotic adjunct regimens, oncology formulations and small drug-induced-injury experiments. It does not establish broad “leaky gut” repair or routine protection from NSAIDs. Commercial support, incompletely reported procurement and outcome definitions limit interpretation; this article states those limits alongside the results (Promac label; Mahmood 2007; Watari 2013).

Table of contents

• Evidence summary
• What zinc-L-carnosine is
• Forms and grades
• How it works
• Hype vs. evidence
• Benefits by claim
• What works and what does not
• Risks and side effects
• Medicine interactions and evidence gaps
• Who should avoid zinc-L-carnosine
• Labeled dose and research protocols
• Animal and in-vitro evidence (excluded from conclusions)
• Independent funding tracing
• Frequently asked questions
• Sources and funding notes

What zinc-L-carnosine is

Zinc-L-carnosine is a 1:1 zinc–carnosine chelate, also called polaprezinc or Z-103. Its proposed mucosal adherence, local zinc delivery and antioxidant mechanisms draw mainly on preclinical research; chemical identity alone does not establish these actions in humans (Li et al., Experimental and Therapeutic Medicine, 2021). (source)

The Li review describes Japanese approval in 1994 and joint development by Hamari and Zeria. That is secondary historical context. The current examined Promac D 75 label is a Zeria product document, revised July 2023, with a gastric-ulcer indication; its formulation’s 2006 market date is distinct from the molecule’s earlier history (Li review; Promac D label).

Forms and grades

A Japanese medicine label and a product sold as a dietary supplement answer different regulatory questions. FDA does not preapprove supplements for safety and effectiveness as it does drugs; a new-dietary-ingredient notification is also distinct from drug approval. Neither this framework nor a shared ingredient name verifies every preparation’s current legal status (FDA supplement overview; FDA questions and answers).

How it works

Local adherence to damaged tissue, antioxidant effects, inflammatory signaling and epithelial repair are proposed mechanisms discussed in the Li and Hewlings reviews. Much of the supporting research uses cells or animals. These hypotheses do not establish targeted zinc delivery, symptom relief or tissue healing in every human preparation. Li includes Broadwell-affiliated authors and reports no funding or competing interests; Hewlings and Kalman report XSTO Solutions funding (Li 2021 review and disclosures; Hewlings and Kalman 2020).

Hype vs. evidence

A claim that zinc-carnosine “heals the gut” can obscure the actual population and outcome. The Mahmood experiment measured the response to a brief indomethacin challenge in ten healthy volunteers. It was not a trial of a general gut-healing diagnosis (Mahmood original).

Mahmood’s randomized crossover used zinc-carnosine 37.5 mg twice daily for seven days, with indomethacin 50 mg three times daily during the final five. The placebo-period mean lactulose:rhamnose ratio rose from 0.35 to 0.88; the zinc-carnosine period did not show that rise. This is a small permeability-surrogate result, not evidence that it prevents ulcers, bleeding or unexplained digestive symptoms. Lonza supplied compound and partly funded the work (full original; PubMed record).

Watari’s separate randomized pilot enrolled twenty long-term low-dose-aspirin users, with ten receiving polaprezinc 150 mg/day for four weeks and ten receiving no polaprezinc. There was no placebo; capsule readers were blinded. Some lesions improved within the treated group, but the between-group changes and capsule-endoscopy score comparison were not significant. The paper declares no conflicts; funding and product-transfer terms were not located. Neither pilot establishes routine clinical NSAID protection (Watari original; Mahmood original).

Benefits by claim

Gastric ulcer and post-endoscopy ulcers

The Shen gastric-ulcer trial randomized 224 participants at ten Chinese centers. Its abstract reports eight-week gastroscopic effective-treatment rates of 81.48% with polaprezinc and 74.31% with rebamipide, p=0.1557; symptom comparisons were also nonsignificant. “Effective-treatment rate” should not be silently converted into complete ulcer healing. The accessible abstract states no competing interests, but the complete outcome definition, equivalence methods, funding and procurement were not verified here. Nonsignificance alone does not prove equal efficacy or safety (original abstract; publisher record).

Jung’s two-hospital Korean trial randomized 218 people after endoscopic submucosal dissection; 210 entered the full analysis and 199 the per-protocol analysis. It compared polaprezinc 75 mg twice daily plus pantoprazole with rebamipide 100 mg three times daily plus pantoprazole for 28 days. Mean ulcer-area reduction was 90.3% versus 91.4%, p=0.523; the proportion in the scarring stage was 9.6% versus 10.4%. The sample-size plan assumed a 5% noninferiority margin, but this article does not independently certify an interval-based noninferiority analysis from the reported comparisons. SK Chemicals funded the trial; the authors declared nothing to disclose. Grade: Moderate for the defined medicinal context, without treating active-comparator findings as independently replicated efficacy for all gastritis or supplement uses (Jung original and funding note; Japanese indication).

H. pylori eradication (adjunct only)

The 2022 synthesis included three trials and 396 participants. It reported H. pylori eradication of 80.4% versus 67.0%, with ITT OR 2.01 (95% CI 1.27–3.21) and per-protocol OR 2.65 (1.55–4.54). Eradication and adverse-event evidence were rated very low certainty. The adverse-event OR of 1.06 (0.55–2.06) does not establish equivalent safety. The review reported no external funding or conflicts; this does not clear its underlying studies’ commercial relationships. Its table uses only Tan’s high-dose and control arms, rather than all 332 randomized participants, and should not be read as a uniform dosing protocol (Mahmoud 2022 synthesis; Tan original).

Tan’s open-label, eleven-hospital Chinese trial randomized 332 people to polaprezinc 75 mg twice daily, 150 mg twice daily, or no polaprezinc, each with the same 14-day omeprazole–amoxicillin–clarithromycin regimen. ITT eradication was 77.0%, 75.9% and 58.6%, respectively; the two polaprezinc doses did not differ significantly. Broadwell, the polaprezinc manufacturer, fully funded the trial and declared no role in its design, analysis or publication. Adverse events and two high-dose withdrawals were reported, including reversible liver-enzyme elevation in one participant. Product-transfer terms were not reported, and differing safety denominators limit a simple all-patient adverse-event comparison (Tan source record; primary publisher report).

Ibrahim’s separate open-label trial randomized 92 people, 46 per arm, and compared ten days of triple therapy plus polaprezinc 75 mg twice daily and bismuth 240 mg twice daily with fourteen days of triple therapy. Its per-protocol analysis reported negative urea-breath tests in 43/46 versus 32/46 participants, p=0.003. Both bismuth and treatment duration differed, so the result cannot isolate zinc-carnosine. The original front matter states support by Synergy Group and declares no conflicts; that group’s identity and product-transfer terms were not verified here. These historical trial regimens are not a universal current first-line recommendation (Ibrahim original, 2022 issue).

Grade: Weak, as a possible adjunct to prescribed eradication therapy. The three-RCT review rated the eradication outcomes very low certainty; it does not establish a replacement for antibiotics or an independently proven benefit. (2022 systematic review)

Oral mucositis in cancer treatment

Mucositis studies include small randomized trials and nonrandomized comparisons, with varying rinse, suspension and lozenge formulations. They should be interpreted individually rather than treated as uniform evidence for swallowed supplements: (original mucositis study; Hewlings & Kalman 2020)

• Doi’s Japanese head-and-neck study prospectively enrolled 32 rinse users, analyzed 31 and compared them with 30 earlier patients. Each 10 mL rinse contained 37.5 mg polaprezinc, was held for one minute four times daily and then spat out. Both groups used sodium gualenate mouthwash; chemotherapy distributions differed. Grade-3 mucosal incidence was 29.0% versus 40.0%, p=0.42, and grade-3 symptom incidence 39.3% versus 60.7%, p=0.18. Neither difference was significant. Zeria partly supported the study with an unrestricted grant; the result does not establish efficacy of a swallowed retail supplement (Doi original).
• Kitagawa’s randomized transplant timing trial enrolled 91 and analyzed 88 participants, with 41 assigned to prevention and 47 controls. A specially prepared 18.75 mg polaprezinc lozenge was sucked and swallowed four times daily, totaling 75 mg/day. Prevention began before chemotherapy; controls started after grade-2 mucositis. The primary grade ≥3 outcome was null: 14.6% versus 10.6%, p=0.572. The secondary grade ≥2 outcome favored prevention: 22.0% versus 44.7%, p=0.025. Assessors were unblinded, conditioning regimens and age differed, and taste/texture withdrawals occurred. JSPS grants 17K08440 and 20K07152 were reported; no potential conflicts were declared. Zeria granules were named, but transfer terms and the payer for acknowledged medical editing were unreported. Nonsignificant engraftment and other-event comparisons do not prove absence of oncology risk (Kitagawa original; PubMed identity).
• The 29% versus 40% rinse comparison above is the same Doi study, not another independent experiment. It appeared online in December 2014 and in the March 2015 issue. The XSTO-funded Hewlings and Kalman review summarizes this literature, but does not provide a separate trial or remove the original study’s limitations (Doi original; review and funding statement).

Grade: Weak / mixed. Small trials provide a possible mucositis signal, but study designs, formulations and populations differ. The frequently quoted 40%→29% result is a nonrandomized, Zeria-supported comparison and was not statistically significant; it cannot establish a routine oncology benefit. (original mucositis study; Hewlings & Kalman 2020)

Functional dyspepsia and GERD

The gastric-ulcer label and the studies reviewed here do not establish efficacy for functional dyspepsia or gastroesophageal reflux disease. Li’s company-affiliated narrative review provides broader medical context, rather than adequate independent confirmation of those specific diagnoses. Grade: Insufficient in the reviewed evidence; this is not a claim that every possible use has been exhaustively tested (Li review; actual labeled indication).

What works and what does not

Risks and side effects

Zinc exposure and copper depletion are important concerns, but they are not the only safety issue. The Japanese product label also lists liver dysfunction and jaundice, with unknown frequencies. Small, short trials cannot estimate uncommon harms or establish safety across all preparations (Promac warnings; NIH zinc guidance).

Medicine interactions and evidence gaps

Who should avoid zinc-L-carnosine

• Anyone taking interacting medicines needs the prescriber’s actual schedule. NIH advises taking quinolone or tetracycline antibiotics at least two hours before, or four to six hours after, zinc; its penicillamine guidance specifies at least one hour apart. The polaprezinc label separately advises avoiding simultaneous penicillamine or levothyroxine administration. These intervals do not provide complete compatibility clearance (NIH interactions; Promac interactions).
• People considering repeated use should account for elemental zinc from food, supplements and prescribed products. The total depends on the actual preparation; it cannot be assumed from the phrase “supplement dose.” Copper deficiency and liver injury require clinical judgment rather than simply keeping a compound dose below a zinc intake limit (zinc intake guidance; product warnings).
• Pregnancy, breastfeeding, childhood and frailty require product-specific medical review. An essential nutrient’s normal dietary role does not establish the safety of polaprezinc or a high-dose combination (Japanese precautions).
• People seeking general “leaky gut” repair or routine NSAID protection should not rely on zinc-L-carnosine: existing small studies examine narrow drug-related settings and do not establish those broader benefits (Mahmood 2007; Watari 2013).
• People with existing copper deficiency, malnutrition or unexplained anemia need particular clinical review; the polaprezinc label reports copper-deficiency-associated anemia and neutropenia, with frequency unknown. Do not routinely add copper or change prescribed treatment on the basis of a supplement article (copper warning; excess zinc).

Labeled dose and research protocols

Animal and in-vitro evidence (excluded from conclusions)

Cell and animal studies inform the biological rationale but were excluded from the human benefit grades. They do not establish symptom relief, clinical bleeding prevention or safety of a retail product. The clinical evidence and labeled warnings are assessed separately.

• Mahmood’s original paper includes rodent injury experiments as well as the separate ten-volunteer crossover. The rodent findings are preclinical evidence, not additional human trials (Mahmood original).
• The cell-migration and proliferation experiments described by Mahmood use human-derived cancer cells and animal cell lines. Human-derived cells are not a human clinical trial; those experiments cannot establish benefit in patients (laboratory methods).
• Li’s Broadwell-affiliated review and the XSTO-funded Hewlings review were used to identify historical and mechanistic context. Their favorable summaries were checked against the pertinent original human results where available, rather than treated as independent replications (Li disclosures; Hewlings disclosures).

Independent funding tracing

Understanding who funded the evidence behind zinc-L-carnosine is essential to interpreting it correctly:

• Zeria, Japan: The actual Promac label identifies Zeria as the medicine’s manufacturer/marketing company. Li’s secondary account describes joint development with Hamari. Doi’s radiation-rinse study explicitly acknowledges a partial unrestricted Zeria grant. A complete contract-by-contract census of the early Japanese trials was not recovered (manufacturer label; historical account; original grant acknowledgment).
• Mahmood’s permeability trial: Reported support includes Wexham Park Gastrointestinal Trust grant 2004/6772, a DDF/Belmont Trust Award, Lonza Nutrition in the USA and M&M Veterinary Health in the USA. Lonza supplied compound, and D. Murray had a Lonza affiliation. R. J. Playford disclosed providing data for an FDA health-claim hearing. Exact cash and supplied-product terms were not stated (full funding and conflict declarations).
• H. pylori and ulcer studies: Broadwell fully funded Tan’s trial; Synergy Group support is acknowledged in Ibrahim’s original report; SK Chemicals funded Jung’s post-endoscopy trial. A no-conflict declaration or sponsor no-role statement does not erase these relationships. Mahmoud’s review reports no external funding or conflicts, but did not create an independently funded trial pool. Shen’s full funding and procurement remain unverified here (Tan; Ibrahim; Jung; review; Shen abstract).
• Reviews and safety education: Li reports no funding or competing interests while listing two Broadwell-affiliated authors. Hewlings and Kalman acknowledge XSTO Solutions funding while declaring no conflicts. The StatPearls toxicity chapter acknowledges HCA Healthcare or affiliate support and declares no relevant financial relationships with ineligible companies. StatPearls is the publisher; its NCBI host does not make the chapter an NIH-authored or financially cleared source. Underlying donors, corporate ownership stakes and unreported product-transfer contracts were not completely reconstructed (Li original; Hewlings original; actual toxicity chapter).

Regulatory status

• Japan: The examined Zeria Promac D 75 label specifies gastric ulcer. Li’s secondary historical account dates earlier polaprezinc approval to 1994; that is distinct from the current formulation’s 2006 marketing date. Label status is not approval of every zinc-carnosine product (official product label; historical review).
• United States: A preparation marketed as a dietary supplement does not acquire FDA drug approval from Japanese medicine status, an ingredient notification or a journal publication. FDA does not preapprove dietary supplements for safety and effectiveness. The original polaprezinc-specific NDI submission and a complete current product-registration census were not verified here (FDA regulatory explanation).
• European Union: A generic EFSA novel-food page does not establish polaprezinc’s authorization or classification. Check the exact formulation and the relevant national/EU record before assuming it may be sold as a supplement or medicine. (source)

Frequently asked questions

Does zinc-L-carnosine heal “leaky gut”?

The cited studies do not establish general “leaky gut” repair. The n=10 permeability crossover and n=20 aspirin-injury pilot concern specific drug exposures and have substantial size, design or financial limitations; they cannot be generalized to unexplained gut symptoms (Mahmood 2007; Watari 2013).

Does zinc-L-carnosine heal gastric ulcers?

Polaprezinc has a Japanese gastric-ulcer medicine indication. Shen reports an eight-week gastroscopic effective-treatment comparison of 81.48% versus 74.31%, p=0.1557; the complete definition was not available here. Jung’s post-endoscopy result describes ulcer-area reduction, not the percentage completely healed. These active-comparator results do not independently establish efficacy of every retail product or prove equivalence from nonsignificance (label; Shen abstract; Jung original).

Does zinc-L-carnosine help eradicate H. pylori?

A possible adjunct signal appears in a three-trial synthesis, but eradication and adverse-event certainty were very low. Broadwell-funded Tan and Synergy-supported Ibrahim studied specific antibiotic regimens; Ibrahim also changed bismuth use and duration. The evidence does not establish standalone eradication or a universal current regimen (synthesis; Tan; Ibrahim; zinc interactions).

Is zinc-L-carnosine safe to take long-term?

Short trial courses do not establish long-term safety. Count elemental zinc from diet and all supplements against the adult UL of 40 mg/day; sustained excess can impair copper status. The UL does not apply to medical treatment under physician supervision; prescribed zinc still warrants appropriate monitoring. The Japanese drug label also warns of liver dysfunction/jaundice and copper deficiency, with unknown frequencies (NIH ODS Zinc; PMDA label).

Is zinc-L-carnosine FDA-approved?

FDA does not preapprove dietary supplements for safety and effectiveness. A Japanese polaprezinc medicine label, a US supplement listing and an ingredient notification are distinct records; none can be silently substituted for FDA approval of a specific treatment. The complete current US product-status census was not verified here (FDA questions and answers; Japanese label).

Does zinc-L-carnosine protect against NSAID-induced gut damage?

Evidence remains weak. A Lonza-supported n=10 permeability crossover and an n=20 aspirin-injury pilot provide preliminary signals, but do not establish routine protection against clinically important NSAID injury (Mahmood 2007; Watari 2013).

Sources and funding notes

• PMDA. Promac D tablets 75 (polaprezinc), Japanese medicine label; indication, dose, adverse effects and interactions. (PMDA label)
• Li M, Sun Z, Zhang H, Liu Z. Recent advances on polaprezinc for medical use. Experimental and Therapeutic Medicine. 2021. No funding or competing interests declared; Li and Zhang have Jilin Broadwell affiliations. Narrative background, not an independent clinical replication. original review
• Hewlings SJ, Kalman DS. A Review of Zinc-L-Carnosine and Its Positive Effects on Oral Mucositis, Taste Disorders, and Gastrointestinal Disorders. Nutrients. 2020. Funded by XSTO Solutions; no conflicts declared. Underlying trial finance not universally cleared. original review
• Shen W, et al. Efficacy and safety of polaprezinc in the treatment of gastric ulcer. Medical Engineering & Physics. 2022. Multicenter active-comparator trial; actual abstract checked. Full endpoint definition, methods, funding and procurement remain unverified here. PubMed abstract
• Jung DH, et al. Comparison of the Efficacy of Polaprezinc Plus Proton Pump Inhibitor and Rebamipide Plus Proton Pump Inhibitor Treatments for Endoscopic Submucosal Dissection-induced Ulcers. Journal of Clinical Gastroenterology. 2021. Funded by SK Chemicals; authors nothing to disclose. Primary endpoint: mean percentage ulcer-area reduction. original report
• Mahmoud A, Abuelazm M, Ahmed AAS, Abdalshafy H, Abdelazeem B, Brašić JR. Efficacy and Safety of Polaprezinc-Based Therapy versus the Standard Triple Therapy for Helicobacter pylori Eradication: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients. 2022. No external funding or conflicts declared; constituent trial finance remains separate. original synthesis
• Ibrahim N, El Said H, Choukair A. Zinc carnosine-based modified bismuth quadruple therapy vs standard triple therapy for Helicobacter pylori eradication: A randomized controlled study. World Journal of Clinical Cases. 2022. Different regimens and durations prevent isolation of the ingredient. Supported by Synergy Group; no conflicts declared; group identity and transfer terms unverified. original report
• Kitagawa J, et al. Multi-institutional randomized timing trial of polaprezinc lozenges during chemotherapy and hematopoietic stem-cell transplantation. International Journal of Cancer. 2021 issue. JSPS grants 17K08440 and 20K07152; no potential conflicts declared. Primary grade ≥3 result null; secondary grade ≥2 positive. original paper
• Doi H, et al. Polaprezinc reduces the severity of radiation-induced mucositis in head and neck cancer patients. Molecular and Clinical Oncology. Online 2014, issue 2015. Prospective/historical comparison; rinse spat out; grade-3 incidence nonsignificant; partial unrestricted Zeria grant. original paper
• Mahmood A, et al. Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. Gut. 2007. PMC1856764 (PMID 16777920)
• Watari I, et al. Effectiveness of polaprezinc for low-dose aspirin-induced small-bowel mucosal injuries as evaluated by capsule endoscopy: a pilot randomized controlled study. BMC Gastroenterology. 2013. No competing interests declared; funding and product-transfer terms unreported. original pilot
• Tan and colleagues. Open-label multicenter randomized H. pylori adjunct trial. PLOS ONE. 2017. Fully funded by manufacturer Broadwell; no sponsor role declared; transfer terms unreported. original trial
• NIH Office of Dietary Supplements. Zinc: Fact Sheet for Health Professionals
• Agnew UM, Slesinger TL. Zinc Toxicity. StatPearls Publishing; updated December 11, 2022. Acknowledges HCA Healthcare or affiliate support; authors declare no relevant financial relationships with ineligible companies. NCBI hosts the chapter; general zinc-toxicity evidence does not measure polaprezinc incidence. chapter record; accessible original chapter
• EFSA. Novel food. General explanation of the safety-assessment and EU authorization framework, not a polaprezinc-specific approval record. Agency and panel financial chains were not exhaustively traced. official framework